Combination therapies for fungal pathogens

Abstract

The present invention relates to methods of treating fungal infections with a drug combination: a first compound that inhibits the activity or expression of the protein FKBP12 and a second compound that inhibits the activity or expression of homoserine dehydrogenase. Evidence indicates that dual inhibitors of proteins FKBP12 and homoserine dehydrogenase are lethal to fungi. Such an approach should be minimally toxic since this combination therapy targets a biosynthetic pathway that is conserved in fungi but not in mammals.

1 . A method for treating a pathogenic fungal infection in a mammalian subject comprising the step of administering to the subject a composition comprising a FKBP12 inhibitor and a homoserine dehydrogenase inhibitor.  
     
     
         2 . The method of  claim 1  wherein said FKBP12 inhibitor is non-immunosuppressive.  
     
     
         3 . The method of  claim 1  wherein said mammalian subject is a human patient.  
     
     
         4 . The method of  claim 3  wherein said human patient is immunocompromised.  
     
     
         5 . The method of  claim 4  wherein said human patient is immunocompromised as a result of drug or radiation treatment.  
     
     
         6 . The method of  claim 4  in which said human patient is a recipient, or is being prepared to become a recipient, of a tissue or organ transplant.  
     
     
         7 . The method of  claim 1  in which said composition comprising a FKBP12 inhibitor and a homoserine dehydrogenase inhibitor are administered in conjunction with an immunosuppressive agent.  
     
     
         8 . The method of  claim 4  wherein said human patient is immunocompromised as a result of diabetes, HIV infection, or other disease or disorder.  
     
     
         9 . The method of  claim 1  wherein said pathogenic fungal infection is caused by a fungus selected from the group consisting of:  Candida  species;  Aspergillus  species;  Cryptococcus neofomans; Blastomyces  species;  Pneumocystis carinii; Coccidioides immitis; Basidiobolus ranarum; Conidiobolus  species;  Histoplasma capsulatum; Rhizopus  species;  Cunninghamella  species;  Rhizomucor  species;  Paracoccidioides brasiliensis; Pseudallescheria boydii; Rhinosporidium seeberi ; or  Sporothrix schenckii.    
     
     
         10 . A method for treating a pathogenic fungal infection comprising providing a mammalian subject infected with a fungus resistant to one or more other antifungal therapies and administering to said subject a composition comprising a FKBP12 inhibitor and a homoserine dehydrogenase inhibitor.  
     
     
         11 . The method of  claim 10  wherein said fungus is resistant to one or more of amphotericin B, an analog thereof or another polyene macrolide antibiotic; flucytosine; griseofulvin; or an imidazole or triazole.  
     
     
         12 . The method of  claim 11  wherein said imidazole or triazole is clotrimazole, miconazole, ketoconazole, econazole, butoconazole, oxiconazole, terconazole, itraconazole or fluconazole.  
     
     
         13 . The method of  claim 10  wherein said composition comprising a FKBP12 inhibitor and a homoserine dehydrogenase inhibitor are administered to said subject in conjunction with at least one other antifungal agent.  
     
     
         14 . A method of  claim 13  in which said other antifungal agent is amphotericin B, an analog thereof or another polyene macrolide antibiotic; flucytosine; griseofulvin; or an imidazole or triazoles such as, e.g., clotrimazole, miconazole, ketoconazole, econazole, butoconazole, oxiconazole, terconazole, itraconazole or fluconazole.  
     
     
         15 . A method for treating a pathogenic fungal infection in a mammalian subject comprising the step of administering to the subject a composition comprising: 
 a) a compound selected from FK506, L-683,590, L-685,818, and rapamycin; and    b) RI-331.